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Accepted: 6 March 2023

DOI: 10.1111/1471-0528.17471

RESEARCH ARTICLE

Impact of coronavirus disease 2019 (COVID-­19) vaccination on


menstrual bleeding quantity: An observational cohort study

Blair G. Darney1,2   | Emily R. Boniface1   | Agathe Van Lamsweerde3  | Leo Han1  |


Kristen A. Matteson4  | Sharon Cameron5   | Victoria Male6   | Juan Acuna7  |
Eleonora Benhar3  | Jack T. Pearson3  | Alison Edelman1

1
Department of Obstetrics & Gynecology,
Oregon Heath & Science University, Portland, Abstract
Oregon, USA Objective: To assess whether coronavirus disease 2019 (COVID-­19) vaccination im-
2
Centro de Investigacion en Salud Poblacional pacts menstrual bleeding quantity.
(CISP), Insituto Nacional de Salud Publica
(INSP), Cuernavaca, Mexico Design: Retrospective cohort.
3
Natural Cycles°, New York, NY, USA Setting: Five global regions.
4
University of Massachusetts Chan Medical Population: Vaccinated and unvaccinated individuals with regular menstrual cycles
School, Worcester, Massachusetts, USA using the digital fertility-­awareness application Natural Cycles°.
5
Department of Obstetrics & Gynecology, Methods: We used prospectively collected menstrual cycle data, multivariable lon-
University of Edinburgh and Chalmers gitudinal Poisson generalised estimating equation (GEE) models and multivariable
Centre, NHS Lothian, Edinburgh, Scotland,
UK multinomial logistic regression models to calculate the adjusted difference between
6
Department of Metabolism, Digestion and vaccination groups. All regression models were adjusted for confounding factors.
Reproduction, Imperial College London, Main outcome measures: The mean number of heavy bleeding days (fewer, no
London, UK change or more) and changes in bleeding quantity (less, no change or more) at three
7
Florida International University School of time points (first dose, second dose and post-­exposure menses).
Public Health, Miami, Florida, USA
Results: We included 9555 individuals (7401 vaccinated and 2154 unvaccinated).
Correspondence About two-­t hirds of individuals reported no change in the number of heavy bleeding
Blair G. Darney, 3181 SW Sam Jackson Park days, regardless of vaccination status. After adjusting for confounding factors, there
Road, UHN-­50, Portland, OR 97239, USA.
Email: darneyb@ohsu.edu were no significant differences in the number of heavy bleeding days by vaccination
status. A larger proportion of vaccinated individuals experienced an increase in total
Funding information bleeding quantity (34.5% unvaccinated, 38.4% vaccinated; adjusted difference 4.0%,
National Institues of Health, Grant/Award
Number: NICHD089957
99.2% CI 0.7%–­7.2%). This translates to an estimated 40 additional people per 1000
individuals with normal menstrual cycles who experience a greater total bleeding
quantity following the first vaccine dose' suffice. Differences resolved in the cycle
post-­exposure.
Conclusions: A small increase in the probability of greater total bleeding quantity
occurred following the first COVID-­19 vaccine dose, which resolved in the cycle
after the post-­vaccination cycle. The total number of heavy bleeding days did not
differ by vaccination status. Our findings can reassure the public that any changes
are small and transient.

K EY WOR DS
bleeding quantity, COVID-­19 vaccination, menstrual cycle, menstruation

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.

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2       DARNEY et al.

1   | I N T RODUC T ION their de-­identified data for research upon registering in the
app, and may remove their consent at any time. Individuals
Menstrual cycles are considered a sign of overall health, a who had consented to the use of their data for research pur-
‘vital sign’ according to the US National Institutes of Health poses (72% of all app users) were sent an in-­app message
(NIH) and medical societies.1,2 Experiencing an unexpected between 7 May and 27 October 2021 explaining that their
change in menstruation can cause concern and even alarm. data could be used for studies about the COVID-­19 vac-
Public and media reports about a possible link between cine and requesting their vaccination status (yes/no), and if
coronavirus disease 2019 (COVID-­19) vaccination and men- yes, vaccine dates (day, month, year) and vaccine brand. To
strual disturbances have highlighted the lack of evidence to be eligible for study inclusion, individuals must have given
respond to such concerns.3,4 Menstrual outcomes were not consent for the use of their anonymised data and reported
included in COVID-­19 vaccine trials,5–­8 limiting the ability their vaccination information. We included individuals aged
of the manufacturers, public health agencies and clinicians 18–­45 years who were at least three cycles post-­pregnancy
to respond to questions about the impact of the vaccine on or from the use of hormonal contraception, were not meno-
menstrual health. There are biologically plausible ways in pausal by self-­report and who had a normal pre-­vaccination
which a vaccine-­elicited immune response could cause men- menstrual cycle (average length of 24–­38 days and menses
strual changes: cytokine production may transiently inter- duration of ≤8 days).
fere with the hypothalamic–­pituitary–­ovarian axis, which Every individual contributed menses data from a mini-
drives the menstrual cycle,9–­12 and/or the activation of local mum of four consecutive cycles. For vaccinated individuals,
immune cells in the endometrium could impact tissue repair we included the three menses immediately prior to vaccina-
at this site, potentially increasing menstrual bleeding.13,14 tion, and at least the menses associated with the first vac-
However, individuals naturally experience inherent and cine dose (designated as ‘first-­dose menses’). If available, we
normal variations in menstrual cycle duration and bleed- also included menses data from the cycles associated with
ing patterns,15,16 making it challenging to isolate COVID-­19 the second vaccine dose (‘second-­dose menses’), as well as
vaccination as a cause. the cycle and menses following vaccination (‘post-­exposure
A growing body of evidence demonstrates that COVID-­19 menses’) to assess the potential resolution of changes. If an
vaccination is associated with a small (less than 1 day) in- individual was vaccinated during their menses, that menses
crease in cycle length but with no change in the duration of was designated as the ‘first-­dose menses’ or ‘second-­dose
menses.17–­21 Other disturbances, such as bleeding quantity menses’, respectively; if they were vaccinated after the com-
or menstrual symptoms, are less well studied. Retrospective pletion of their menses, the following menses was designated
studies have identified that changes in bleeding quantity may as the ‘first-­or second-­dose menses’. For unvaccinated in-
occur with vaccination, but these studies are not designed to dividuals (control group), we included menses data from
determine whether vaccination is the main factor associated four to six cycles from a similar time period, depending on
with these changes, as they lack a comparison group and use the volume of data recorded, to serve as the notional pre-­
retrospective self-­reported data.22–­24 vaccination period, first-­dose menses, second-­dose menses
The objective of this study is to estimate the association and post-­exposure menses. Individuals without data beyond
of COVID-­19 vaccination on menstrual bleeding quantity menses associated with the first vaccination dose were ex-
among individuals with normal menstrual cycles (i.e. cycle cluded from the analyses of later time points.
lengths of 24–­38 days with menses of ≤8 days). We examine Individuals using the Natural Cycles° application can
changes in the number of heavy bleeding days and in total choose whether or not they want to track their menstrual
bleeding quantity using data from a retrospective cohort ‘flow’ or menstrual bleeding quantity; it is not a required
study using prospectively collected menstrual cycle data and variable and thus many individuals have no or incomplete
an unvaccinated comparison group. data for menstrual bleeding quantity. We excluded individ-
uals with more than 1 day of missing bleeding quantity data
during the three pre-­vaccination menses or during the three
2   | M ET HODS post-­vaccination menses of interest. Thus, in total, individ-
uals were allowed up to 4 days of missing bleeding quantity
We conducted a retrospective cohort study using vaccination data to be included in the final data set: one during the pre-­
and menstrual cycle data from individuals using the fertil- vaccination period and one for each of the post-­vaccination
ity awareness application Natural Cycles° (Natural Cycles°, menses analysed.
New York, NY, USA). Cycle data ranged from October 2020 Our primary exposure was COVID-­19 vaccination, as re-
to May 2022; initial COVID-­19 vaccinations were received ported by individuals using the Natural Cycles° application:
between January 2021 and April 2022. Individuals using individuals recorded their vaccination date(s) or confirmed
Natural Cycles° prospectively track their physiological their unvaccinated status. We also classified vaccinated in-
data as a non-­hormonal pregnancy prevention or planning dividuals by the mechanism of action of the vaccine that
method, with no concurrent use of any hormonal contracep- they received: mRNA (Pfizer-­BioNTech and Moderna), ad-
tive method. Details on variables tracked by Natural Cycles° enovirus vector (Astrazeneca, Johnson & Johnson/Janssen,
are reported elsewhere.15 Users may consent to the use of Covishield and Sputnik) and inactivated virus (Covaxin,
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COVID19 VACCINE AND MENSTRUAL BLEEDING QUANTITY   
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Sinopharm and Sinovac). One individual who received vs parous), education (an undergraduate or higher degree vs
the protein subunit-­mediated Novavax vaccine could not less education) and relationship status (in a steady relation-
be classified with the other vaccine mechanisms, and was ship or not).
therefore grouped with individuals with unspecified vaccine The Oregon Health & Science University Institutional
brand. Review Board (study no. 00023204, approved 6 August 2021)
Individuals report their daily bleeding quantity as and the UK's Reading Independent Ethics Committee (study
‘spotting’, ‘light’, ‘medium’ or ‘heavy’. We assessed men- no. 230721, approved 23 July 2021) approved the study pro-
strual bleeding quantity in two ways: the number of heavy tocol. De-­identified data were used under a data use agree-
bleeding days and the total bleeding quantity, i.e. the ordi- ment with Natural Cycles°. No members of the public were
nal sum of bleeding scores with spotting scored as 1, light directly involved in this analysis, although the research was
scored as 2, medium scored as 3, and heavy scored as 4. For developed in response to public reports of menstrual distur-
each post-­vaccination menses (first-­dose menses, second-­ bances following COVID-­19 vaccination.
dose menses and post-­exposure menses), we calculated the
within-­individual change from the median of the three pre-­
vaccination menses. We then categorised the change in the 2.1  | Analysis
number of heavy bleeding days as fewer days, no change
or more days, and categorised the change in total bleeding We examined sociodemographic characteristics of the study
quantity as less bleeding, no change or more bleeding. We sample, by vaccination status and overall. We compared
chose to categorise these changes rather than analyse them the changes in the number of heavy bleeding days and total
as numeric because the units of the total bleeding quantity bleeding quantity for the first-­dose, second-­dose and post-­
outcome are not interpretable, and no clinical meaning ex- exposure menses using Pearson's chi-­square test, adjusting
ists for a fractional unit for either outcome. We therefore had the p-­values to reflect our significance level of 0.008. We
two outcomes measured at three time points each (the first-­ then created histograms of the raw, uncategorised change
dose menses, second-­dose menses and post-­exposure men- in number of heavy bleeding days and total bleeding quan-
ses): (1) the change in number of heavy bleeding days; and (2) tity by vaccination group and tabulated the change in heavy
the change in total bleeding quantity. We used a Bonferroni-­ bleeding days. We developed multivariable longitudinal
adjusted significance level of 0.008 to account for multiple Poisson general estimating equation (GEE) models for all
comparisons for these six total outcomes and thus report three heavy bleeding day outcomes. GEE models included
99.2% confidence intervals. No relevant core outcome set ex- an offset for duration of menses, and an interaction between
ists or is in development to address menstrual changes, and time (pre-­/post-­vaccination) and vaccination status to deter-
therefore none were used for these analyses. mine the effect of vaccination, i.e. the adjusted difference in
We included sociodemographic information collected by the change in number of heavy bleeding days between vac-
Natural Cycles° using in-­app messages. Individuals using cination groups. We then plotted the predicted number of
the app are required to input some demographic variables heavy bleeding days before and after vaccination for both
(such as age and country of residence) and other data are op- groups. For the three total bleeding quantity outcomes, we
tional (such as body mass index, BMI), whereas additional developed multivariable multinomial logistic regression
sociodemographic data are supplied voluntarily as part of models using no change as the base outcome, then calcu-
research requests and are thus not supplied by all app users. lated the adjusted predicted probability of each outcome
As such, some sociodemographic variables have a large vol- (less bleeding, no change or more bleeding) for each vaccina-
ume of non-­ignorable missing data (for details on ‘missing- tion group and the adjusted difference between groups. All
ness’, see Table  S1). As a result, we included ‘missing’ as a regression models were adjusted for age, race and ethnicity,
category in multivariable analyses. We classified age at the parity, BMI, education, relationship status and global region.
beginning of the first cycle: 18–­24, 25–­29, 30–­34, 35–­39 or Models for the second-­dose menses and post-­exposure men-
40–­44 years. Individuals reported their race and ethnicity ses were also adjusted for time between the first and second
as Asian, black, Hispanic, Middle Eastern or North African, vaccine doses.
Native Hawaiian or Pacific Islander, or white. As a result We conducted nine sensitivity analyses to confirm our
of the small sample sizes, we collapsed race and ethnicity results. First, we compared the sociodemographic charac-
categories into a binary variable for multivariable analyses. teristics of individuals included in the study with those who
We categorised global region as UK and Channel Islands, were excluded for missing bleeding quantity data. Second,
Europe, USA and Canada, Australia and New Zealand or we compared the change in the number of heavy bleeding
other. Individuals from Sweden made up the majority of days and total bleeding quantity for the first-­and second-­
users in Europe (51%), whereas individuals from Brazil made dose menses by vaccine mechanism of action (mRNA,
up the majority of users in the ‘other’ category (62%). We adenovirus vector or inactivated virus), by type of mRNA
grouped BMI into underweight, normal weight, overweight vaccine and by timing of vaccination (during menses vs
and obese categories, and collapsed the underweight and after menses). Third, although the data did not meet the
normal weight groups for multivariable analyses because of missing-­at-­random assumption required for imputation
the small sample sizes. We also included parity (nulliparous techniques, we completed 500 iterations of imputation
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4       DARNEY et al.

and weighting with covariate balancing propensity scores of individuals experienced no change, whereas approxi-
using bootstrapped standard errors to confirm that our mately 20% experienced fewer heavy bleeding days and 20%
findings were not biased by missing data or by differences experienced more heavy bleeding days. After adjustment in
in the characteristics of the vaccination groups. Fourth, we multivariable models, there were still no significant differ-
excluded any individuals with polycystic ovary syndrome ences by vaccination status during the first-­and second-­dose
(PCOS), endometriosis or thyroid disorder (n  =  454). menses (Figure 2).
Fifth, we excluded any individual who used emergency When examining the change in total bleeding quan-
contraception during the study period (n = 472). Sixth, we tity pre-­and post-­vaccination (less bleeding, no change
excluded individuals with any pre-­vaccination cycles out- or more bleeding), we found differences between the
side the normal length of 24–­38 days (n = 1420). Seventh, vaccinated and unvaccinated control groups (Figure  S2;
we excluded individuals who had received both vaccine Table 2). Vaccinated individuals were more likely to report
doses since their previous menses (n  =  422). Eighth, we more bleeding overall than their unvaccinated counter-
excluded individuals with any missing bleeding quan- parts during both the first-­dose menses (38.3% vs 34.8%,
tity data during the pre-­ vaccination menses, or first-­ p  =  0.027) and the second-­dose menses (39.8% vs 35.5%,
dose, second-­dose or post-­exposure menses (n = 4090 for p < 0.001). The proportion of individuals who experienced
first-­dose menses, n  =  3050 for second-­dose menses and no change in total bleeding quantity was roughly 18% for
n = 3020 for post-­exposure menses). Finally, we included both vaccinated and unvaccinated groups at both time
individuals with pre-­vaccination menses durations of 9 or points. The differences between groups were no longer sta-
10 days (who had previously been excluded; n  =  93). We tistically significant in the post-­exposure cycle. After ad-
used Stata 15.1 (StataCorp LLC, College Station, TX, USA) justment in multivariable models, the predicted probability
for all analyses. of experiencing more total bleeding quantity was higher
in the vaccinated group compared with the unvaccinated
control group: 4.0% higher (99.2%  CI 0.7%–­7.2%) for the
3   | R E SU LT S first-­dose menses and 3.8% higher (99.2%  CI 0.2%–­7.3%)
for the second-­dose menses (Table S4). This translates to
Out of 42 095 users, 9555 individuals (7401 vaccinated and approximately 40 additional people per 1000 individuals
2154 unvaccinated) representing 229 320 menses met the with normal cycles who will experience a greater total
inclusion criteria (Figure 1). The overall cohort was under bleeding quantity as a result of vaccination. Again, this
the age of 35 years (80.4%), nulliparous (77.4%), had at difference was no longer significant in the post-­exposure
least a college degree (67.8%) and was in a steady relation- menses: 2.8% higher for vaccinated individuals (99.2% CI
ship (69.7%) (Table  1). Most individuals were located in −0.8%–­6.3%; data not shown).
the UK (32.4%), Europe (31.2%) or the USA and Canada We found no major differences in the change in number
(30.1%). Among vaccinated individuals, the majority re- of heavy bleeding days or the total bleeding quantity when
ceived mRNA vaccines: 66.7% Pfizer-­BioNTech and 17.9% comparing individuals who received an mRNA vaccine
Moderna. Vaccinated individuals were more likely to with individuals who received an adenovirus vector vaccine
have at least an undergraduate degree (71.4%, compared during either the first-­or second-­dose menses (Figures  S3
with 55.3% among unvaccinated individuals). The char- and S4), and there were no differences in any bleeding out-
acteristics of individuals included in the study were simi- come between the two mRNA vaccines (data not shown).
lar to those excluded for missing bleeding quantity data The number of individuals who received an inactivated virus
(Table S2); the majority of participants excluded for miss- (n  =  44 for first-­dose menses and n  =  31 for second-­dose
ing bleeding quantity data were excluded for missing data menses) was too small to draw conclusions. We also found
in the pre-­vaccination period (8851 out of 10 325 excluded, no meaningful differences in our outcomes when examined
86%; data not shown), and thus a baseline could not be by timing of vaccination (during menses vs after completion
established. The sample size for the vaccinated group of menses; Figures S5 and S6).
was considerably smaller for the second-­ dose menses The sensitivity analysis imputing missing data and
(n = 5288; Figure 1) for a variety of reasons: some individu- weighting the sample to balance vaccination groups on
als (2.0% of vaccinated) received the single-­dose Johnson all sociodemographic variables did not alter our unad-
& Johnson/Janssen vaccine; some did not receive or did justed or adjusted results in a meaningful way (Table S5).
not record information about their second dose (22.6%); Nor did the sensitivity analyses excluding individuals: (1)
and some (3.1%) received their second dose after their last with PCOS, endometriosis or thyroid disorders; (2) who
cycle of tracked data. used emergency contraception; (3) with pre-­vaccination
The unadjusted change in the number of heavy bleed- cycle lengths outside the normal range; (4) who received
ing days reported did not differ between the vaccinated and two vaccine doses prior to a single menses; or (5) with any
unvaccinated control group for any of the post-­vaccination missing bleeding quantity data. The final sensitivity anal-
menses (Figure S1; Tables 2 and S3). Regardless of vaccination ysis including individuals with slightly longer durations
status (actual or notional) for the first-­dose menses, second-­ of pre-­vaccination menses (9–­10 days) also did not change
dose menses and post-­exposure menses, approximately 60% the results.
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COVID19 VACCINE AND MENSTRUAL BLEEDING QUANTITY   
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Eligible (n= 42 095)


Identification

Not included (n= 32 540)


No logged cycle data (n= 332)
< 3 pre-vaccination cycles (n= 10 871)
No vaccination cycle data (n= 1061)
Pre-vaccination menses length > 10
days (n= 601)
Non-consecutive cycles (n = 2675)
< 3 cycles post-pregnancy (n= 1909)
< 3 cycles post-hormonal
Inclusion contraception (n= 2982)
Menopausal (n= 30)
Outside of age range (n= 2)
Average pre-vaccination cycle length
< 24 or > 38 days (n= 1659)
> 1 missing day of bleeding quantity
data for 3 pre-vaccination menses or
for post-vaccination outcome menses
(n= 10 325)
Pre-vaccination menses length of 9-10
days (n= 93)a

Included in dataset (n= 9555)

Reported COVID-19 Vaccination Reported unvaccinated for COVID-19


1st dose mensesb: n= 7401 Notional 1st dose menses: n= 2154
Analysis Notional 2nd dose menses: n= 2134
2nd dose mensesc: n= 5288
Post-exposure mensesd: n= Notional post-exposure menses: n=
5127 2106

F I G U R E 1   STROBE flow diagram. aIndividuals with pre-­vaccination menses of 9–­10 days in duration were excluded from all primary analyses but
were then later included for a sensitivity analysis. b1st dose menses indicates the menses during or immediately following receipt of the first COVID-­19
vaccine dose. c2nd dose menses indicates the menses during or immediately following receipt of the second COVID-­19 vaccine dose. dPost-­exposure
menses indicates the menses of the cycle following the second-­dose menses

4   | DISC US SION days tracked, regardless of vaccination status. After adjust-


ing for confounding factors, we found no significant differ-
4.1  |  Main findings ences in the number of heavy bleeding days by vaccination
status. However, a larger proportion of vaccinated individu-
We used prospectively tracked menstrual cycle bleeding data als experienced an increase in total bleeding quantity. Of the
to assess changes in the number of heavy bleeding days and unvaccinated individuals, 34.5% experienced a greater bleed-
total bleeding quantity (menstrual ‘flow’) in individuals who ing quantity following the first vaccine dose, compared with
received COVID-­19 vaccination, as compared with an un- 38.4% among the vaccinated individuals: representing an ad-
vaccinated control group. Overall, about two-­thirds of indi- justed increase of 4.0% (99.2% CI 0.7%–­7.2%) in the probabil-
viduals reported no change in the number of heavy bleeding ity of a greater bleeding quantity following the first vaccine
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6       DARNEY et al.

T A B L E 1   Study participant characteristics (n = 9555), by vaccination status

Characteristic Unvaccinated Vaccinated Overall p


n 2154 7401 9555
Age group (years)
18–­24 423 (19.6) 745 (10.1) 1168 (12.2) <0.001
25–­29 724 (33.6) 2571 (34.7) 3295 (34.5)
30–­34 611 (28.4) 2609 (35.3) 3220 (33.7)
35–­39 296 (13.7) 1109 (15.0) 1405 (14.7)
40–­4 4 100 (4.6) 367 (5.0) 467 (4.9)
BMI category
Underweight 52 (2.4) 196 (2.7) 248 (2.6) 0.004
Normal weight 951 (44.2) 3468 (46.9) 4419 (46.3)
Overweight 277 (12.9) 993 (13.4) 1270 (13.3)
Obese 123 (5.7) 486 (6.6) 609 (6.4)
No data 751 (34.9) 2258 (30.5) 3009 (31.5)
Race and ethnicity
Asian 7 (0.3) 73 (1.0) 80 (0.8) <0.001
Black 46 (2.1) 54 (0.7) 100 (1.1)
Hispanic 47 (2.2) 145 (2.0) 192 (2.0)
Middle Eastern or North African 7 (0.3) 19 (0.3) 26 (0.3)
Native Hawaiian or Pacific Islander 3 (0.1) 15 (0.2) 18 (0.2)
Non-­Hispanic white 829 (38.5) 2926 (39.5) 3755 (39.3)
No data 1215 (56.4) 4169 (56.3) 5384 (56.4)
Parity
Nulliparous 1513 (70.2) 5882 (79.5) 7395 (77.4) <0.001
Parous 332 (15.4) 824 (11.1) 1156 (12.1)
No data 309 (14.4) 695 (9.4) 1004 (10.5)
Education
Less than college degree 548 (25.4) 1093 (14.8) 1641 (17.2) <0.001
Completed college degree 1190 (55.3) 5284 (71.4) 6474 (67.8)
No data 416 (19.3) 1024 (13.8) 1440 (15.1)
Relationship status
Not in steady relationship 313 (14.5) 962 (13.0) 1275 (13.3) <0.001
In steady relationship 1423 (66.1) 5236 (70.8) 6659 (69.7)
No data 418 (19.4) 1203 (16.3) 1621 (17.0)
Geographic region
UK 521 (24.2) 2574 (34.8) 3095 (32.4) <0.001
Europe 519 (24.1) 2466 (33.3) 2985 (31.2)
USA and Canada 931 (43.2) 1941 (26.2) 2872 (30.1)
Australia and New Zealand 152 (7.1) 222 (3.0) 374 (3.9)
Other 31 (1.4) 198 (2.7) 229 (2.4)
Vaccine type
Pfizer 0 (0) 4938 (66.7) 4938 (51.7) N/Aa
Moderna 0 (0) 1322 (17.9) 1322 (13.8)
Johnson & Johnson 0 (0) 151 (2.0) 151 (1.6)
Astrazeneca/adenovirus vector 0 (0) 650 (8.8) 650 (6.8)
Whole/inactivated virus 0 (0) 44 (0.6) 44 (0.5)
Unspecifiedb 0 (0) 296 (4.0) 296 (3.1)
Unvaccinated 2154 (100) 0 (0) 2154 (22.5)

Note: p-­values represent differences by vaccination status using Pearson's chi-­square test.
a
No statistical test performed.
b
Unspecified group contains one individual who received the protein subunit-­based Novavax vaccine.
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COVID19 VACCINE AND MENSTRUAL BLEEDING QUANTITY    |
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T A B L E 2   Changes in number of heavy bleeding days from the median of three pre-­vaccination menses to the first-­dose menses, second-­dose menses
and post-­exposure menses, by vaccination status

Difference from pre-­


Outcome vaccination to: Category Unvaccinated Vaccinated pa
Number of heavy First-­dose mensesb n 2154 7401 1.000
bleeding days Fewer heavy days 420 (19.5) 1371 (18.5)
No change 1304 (60.5) 4630 (62.6)
More heavy days 430 (20.0) 1400 (18.9)
c
Second-­dose menses n 2134 5288 1.000
Fewer heavy days 390 (18.3) 916 (17.3)
No change 1299 (60.9) 3270 (61.8)
More heavy days 445 (20.9) 1102 (20.8)
d
Post-­exposure menses n 2106 5127 1.000
Fewer heavy days 400 (19.0) 908 (17.7)
No change 1282 (60.9) 3197 (62.4)
More heavy days 424 (20.1) 1022 (19.9)
Total bleeding First-­dose mensesb n 2154 7401 0.027
quantity Less quantity 1013 (47.0) 3208 (43.4)
No change 392 (18.2) 1356 (18.3)
More quantity 749 (34.8) 2837 (38.3)
Second-­dose mensesc n 2134 5288 <0.001
Less quantity 983 (46.1) 2161 (40.9)
No change 393 (18.4) 1020 (19.3)
More quantity 758 (35.5) 2107 (39.8)
Post-­exposure mensesd n 2106 5127 0.157
Less quantity 973 (46.2) 2192 (42.8)
No change 369 (17.5) 969 (18.9)
More quantity 764 (36.3) 1966 (38.4)

Note: Data are n (%).


a
p-­values are adjusted to account for six comparisons; values below 0.05 represent statistically significant differences.
b
First-­dose menses indicates the menses during or immediately following receipt of the first COVID-­19 vaccine dose.
c
Second-­dose menses indicates the menses during or immediately following receipt of the second COVID-­19 vaccine dose.
d
Post-­exposure menses indicates the menses of the cycle following the second-­dose menses.

dose in multivariable analyses. For the second dose, 35.9% of self-­reported perceptions of changes in bleeding that were previ-
the unvaccinated individuals compared with 39.7% of the vac- ously reported). Our outcome measures used counts of heavy
cinated individuals experienced a greater bleeding quantity bleeding days and an ordinal measure of total bleeding quantity,
following vaccination: a 3.8% higher (99.2%  CI 0.2%–­7.3%) which are less subjective than retrospective reports of ‘more’ or
adjusted probability for the second-­dose menses in multivari- ‘less’ bleeding (as previously reported). We also include an un-
able analyses. This translates into an estimated additional 40 vaccinated control group that allows us to isolate the relation-
people per 1000 individuals with normal cycles (the difference ship of vaccination and menstrual bleeding quantity.
between 342/1000 unvaccinated and 384/1000 vaccinated) The limitations of our study include a lack of complete
who will experience a greater total bleeding quantity with sociodemographic data to fully understand the racial/ethnic
the first vaccine dose as a result of vaccination. The bleeding and gender-­identity diversity in our sample. Our study popu-
quantity recorded by vaccinated and unvaccinated groups no lation is also of lower BMI and higher education than is found
longer differed by the time of the post-­exposure cycle. in general populations. Further, our sample is global, but the
USA, UK and Europe are over-­represented. To isolate the
association of the COVID-­19 vaccine and menstrual bleed-
4.2  |  Strengths and limitations ing changes, our study population includes individuals with
normal menstrual characteristics pre-­vaccine. Future studies
The strengths of this study include a large global sample with should focus on key subgroups, including contraceptive users,
geographic diversity and prospectively tracked bleeding data: menopausal individuals, people using gender-­affirming hor-
users tracked bleeding quantity each day (vs the retrospective monal therapy and those with non-­clinically normal cycles
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8       DARNEY et al.

F I G U R E 2   Predicted number of heavy bleeding days for the median of three pre-­vaccination menses and the first-­dose (left), second-­dose (centre)
and post-­exposure (right) menses. Estimates are from longitudinal GEE models with an offset for menses duration, an interaction between vaccination
status and pre-­/post-­vaccination timing, and adjusted for age, BMI, educational attainment, parity, relationship status, global region and time between
doses (second dose and post-­exposure only). Unvaccinated users are shown in red, vaccinated users are shown in blue and error bars represent the
99.2% CIs. First-­and second-­dose menses indicate the menses during or immediately following receipt of the first and second vaccine dose, respectively.
Post-­exposure menses indicates the menses of the cycle following the second-­dose menses

or menses at baseline. Our sample may also be subject to se- bleeding patterns,25–­27 and vaccination status is self-­reported
lection bias if individuals who experienced bleeding changes and not verified, although we do have dates and vaccine
were more likely to provide information on their vaccina- brands, and the self-­report of vaccine status and timing has
tion status than individuals with no changes. However, the been shown to be a good surrogate for clinical data.28
existence of a sizable unvaccinated cohort suggests that our
study population is willing to contribute to menstrual cycle
research, regardless of the potential impact of the vaccine. 4.3  |  Interpretation in light of other evidence
We recognise that more questions remain regarding dif-
ferent aspects of menstrual bleeding, but we are limited by A study using the retrospective recall of changes in bleed-
the variables collected within the tracking application. On ing quantity following COVID-­19 vaccination and no com-
the one hand, the app utilises the gold standard for real-­time parison group found that 42% of those reporting regular
menstrual cycle tracking and identifying heavy bleeding, menstrual cycles prior to vaccination reported experienc-
which is based on an individual's self-­assessment.16 On the ing heavier bleeding following vaccination, relative to their
other hand, the units of our ordinal measure of total bleed- bleeding before vaccination.24 Another study also using
ing quantity have no real numerical interpretation and are retrospective recall of menstrual changes but including
not necessarily comparable with the self-­reported outcomes an unvaccinated pre-­ /post-­
comparison group (surveyed
of ‘more’ or ‘less’ bleeding reported previously. However, this individuals were asked about outcomes before and after
outcome enables us to note whether a change in bleeding vaccination) found that menstrual disturbances did fol-
quantity or ‘menstrual flow’ has occurred or not in relation low vaccination. However, this study also identified that
to vaccine exposure, which is a critical knowledge gap and more than one-­third of their total participants (vaccinated
an important outcome of documented interest to the public. and control) experienced disturbances even prior to vac-
Additionally, individuals are not required to track bleeding cination or for controls over a similar time period.22 This
quantity data in the app, which limited our sample size. We finding is consistent with our results that over one-­t hird of
examined the ‘missingness’ of the data between included and individuals, regardless of vaccination status, had a greater
excluded individuals and found no changes in our results. We bleeding quantity. A retrospective study without an unvac-
have no measure of COVID-­19 disease, which may impact cinated comparison group reported that menstrual changes
14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17471 by INASP/HINARI - MONTENEGRO, Wiley Online Library on [14/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COVID19 VACCINE AND MENSTRUAL BLEEDING QUANTITY   
   9|

were more frequent following the second dose than the first analyses. BGD and ERB drafted the manuscript. AE, EB,
dose;23 another found no differences in menstrual flow.18 JTP, AVL, KAM, SC, LH, JA, and VM provided substantive
Our study highlights the importance of an unvaccinated intellectual contributions to the manuscript.
comparator group: bleeding variability was high, regardless of
receiving a vaccine. With the inclusion of an unvaccinated con- AC K N O​W L E​D G E​M E N T S
trol group and accounting for confounding factors, we found no We thank the individuals who shared their menstrual ex-
differences in the number of heavy bleeding days by vaccina- periences around the COVID-­19 vaccine, whose voices in-
tion status, but we did find that a small but significantly larger formed our work. We also acknowledge the contribution to
proportion of vaccinated individuals experienced a greater science that would not have been possible without the users
total bleeding quantity in the cycle of their first-­and second-­ of Natural Cycles who granted permission to share their de-­
vaccine doses, compared with unvaccinated individuals. This identified data.
difference was resolved by the time of the cycle following ex-
posure to COVID-­19 vaccination. Previous research using the F U N DI N G I N F OR M AT ION
Natural Cycles° app data found a small increase in cycle length Research reported in this publication was externally peer-­
and no difference in menses length associated with COVID-­19 reviewed and funded by the Eunice Kennedy Shriver
vaccination.20,21 This study adds to the growing body of evi- National Institute of Child Health and Human Development
dence of time-­limited menstrual disturbances associated with (NICHD) and the NIH Office of Research on Women’s
COVID-­19 vaccination at a population level of reproductive-­ Health (NIH NICHD089957 Supplement). The funder
aged individuals with previously regular menstrual cycles. played no role in the study design, analysis or interpretation
The impact of COVID-­19 disease on menstrual distur- of the data presented in this article.
bances in unvaccinated individuals is less well defined, which
is the relevant counterfactual for those hesitant to vaccinate C ON F L IC T OF I N T E R E S T S TAT E M E N T
themselves or family members because of concerns about AE reports honoraria and travel reimbursement from
menstrual disturbances. Changes in menstrual cycles were American College of Obstetricians and Gynecologists
reported by 16% of a cohort who had COVID-­19 disease prior (ACOG), World Health Organization (WHO) and
to the availability of vaccines (2020), compared with those Gynuity for committee activities, and honoraria for peer
who had COVID-­19 disease in 2020 and reported no change review from the Karolinska Institute. AE receives roy-
in menstrual cycles. In two studies carried out prior to the alties from UpToDate, Inc. Oregon Health & Science
availability of vaccines, 16% or 28% of menstruating people University (OHSU) receives research funding from the
with COVID-­19 disease reported menstrual changes, with OHSU Foundation, Merck, HRA Pharma and NIH, for
changes associated with more severe disease.25, 26 In a cohort which AE is the principal investigator. BGD reports hon-
of people with long COVID, more than 30% of menstruating oraria and travel reimbursement from ACOG and the
participants reported some kind of menstrual disturbance.27 Society for Family Planning (SFP) for board, committee
Those who reported menstrual changes also reported more and mentorship activities. OHSU receives research fund-
severe COVID-­19 symptoms.25 Finally, COVID-­19 disease ing from Merck/Organon and the Office of Population
carries serious morbidity and mortality risks to unvaccinated Affairs (OPA)/Department of Health and Human
individuals, which must be considered when discussing con- Services (DHHS), for which BGD is the principal inves-
cerns about menstrual disturbances and vaccination. tigator. OHSU receives research funding from the OHSU
The development of core outcome sets and regulatory Foundation, the Bill & Melinda Gates Foundation, the
support to include these core outcomes in future vaccine American Board of Obstetrics and Gynecology (ABOG),
development studies would aid in providing foundational the American Society for Reproductive Medicine (ASRM)
information on a critical patient-­reported outcome. and the NIH, for which LH is the principal investigator.
In conclusion, we find a small but statistically significant EB, AVL and JTP are employees of Natural Cycles°. KAM
increase (4.0%) in the adjusted probability of a greater total reports honoraria and travel reimbursement from ABOG
bleeding quantity following the first COVID-­19 vaccine dose, and travel reimbursement from ACOG. The Women &
compared with an unvaccinated comparison group. This dif- Infants Hospital received funding from Myovant for con-
ference translates into an estimated additional 40 people per sulting work performed by KAM on outcome measures for
1000 individuals with normal cycles experiencing a greater heavy menstrual bleeding. ERB did not report any poten-
bleeding quantity post-­vaccine that is resolved by the time of tial conflicts of interest. JA reports honoraria from Natural
the post-­vaccination cycle. We found no difference in the total Cycles. VM reports research funding from Borne, payment
number of heavy bleeding days by vaccination status. Our for acting as an external examiner for the Universities of
findings can inform patients and help providers in counsel- Cambridge, Leeds, Swansea and Trinity College Dublin,
ling about what to expect following a COVID-­19 vaccination. payment for articles written for the Guardian newspaper,
royalties received for contribution to Immunology 9th
AU T HOR C ON T R I BU T ION S edition (Elsevier) and support to attend the 16th Vaccine
AE conceived of the study and secured funding. AE, ERB, Congress. Completed disclosure of interests form available
and BGD developed the analysis plan and conducted to view online as supporting information.
14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17471 by INASP/HINARI - MONTENEGRO, Wiley Online Library on [14/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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10       DARNEY et al.

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